tbuckley/cabot-search huggingface dataset:
Abstract 5131: Deep learning-based tumor microenvironment cell types mapping from H&amp;E images of lung adenocarcinoma using spatial transcriptomic data
Authors: Hongyoon Choi, Kwon Joong Na, Jaemoon Koh, Young Tae Kim
Journal: Cancer Research (2022)

Abstract Purpose Spatial characterization of cell types of the tumor microenvironment (TME) is a key to finding new targets as well as developing biomarkers for immuno-oncology treatment. Here, we develop and validate a deep learning model trained by integrating H&amp;E images of lung adenocarcinoma and spatial transcriptomic data to decipher spatial mapping of multiple cell types in TME only using H&amp;E images. Methods A total of 21 H&amp;E images combined with spatial transcriptomic data of lung adenocarcinoma were used to develop a model. As each spot of spatial transcriptomic data consisted of a few cells, the cell types were inferred by CellDART, a domain adaptation-based method to estimating five cell types defined by single cell RNA-seq (scRNA-seq) data - B, T/NK, myeloid cells, fibroblasts, and epithelial cells. A convolutional neural network using H&amp;E image patches as inputs was developed to predict the cell type scores for each corresponding spot. For the external validation, the model estimated the cell type scores from H&amp;E-stained tissue image patches of lung adenocarcinoma of the Cancer Genome Atlas (TCGA-LUAD). Furthermore, the model inferred cell types from H&amp;E images of lung adenocarcinoma tissues acquired by different patients and the results were compared with immunohistochemistry. Results The cell types inferred by the model using H&amp;E image patches were significantly correlated with those derived by spatial transcriptomic data as an internal validation. The mean value of the deep learning-based cell types scores estimated by the TCGA-LUAD tissue images was significantly correlated with the cell type scores estimated by bulk RNA-seq data of corresponding TCGA data. When cell type inference maps of independent lung adenocarcinoma H&amp;E images were spatially co-registered with immunohistochemistry slides, including CD3, CD20, and CD68, pixel-wise correlation analysis revealed positive significant correlations. Conclusions A deep learning model to infer spatial cell types of tumor microenvironment using H&amp;E images was developed. The results of cell type scores were positively correlated with bulk RNA-seq-based immune cell enrichment scores and pixelwise analyses on immunohistochemistry images using typical cell type markers. This approach can provide objective and flexible deep learning-based models for characterizing tumor microenvironment. Citation Format: Hongyoon Choi, Kwon Joong Na, Jaemoon Koh, Young Tae Kim. Deep learning-based tumor microenvironment cell types mapping from H&amp;E images of lung adenocarcinoma using spatial transcriptomic data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5131.
Abstract 394: Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance
Authors: Kofi Kyenku Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan Bowen, Daqing Wu, Valerie Odero-Marah
Journal: Cancer Research (2022)

Abstract The aryl hydrocarbon receptor (AhR) is a nuclear transcription factor and xenobiotic sensor reported to mediate diet-induced obesity and is upregulated in high-grade prostate cancer (PCa). Previously published data from our lab shows that AhR protein is overexpressed and constitutively active in castration-resistant prostate cancer cells. Physiologically relevant leptin concentration is proportional to BMI and it is secreted by adipose cells to inhibit hunger under normal circumstances. Our preliminary results suggest that obesity-associated leptin concentrations desensitize PCa cells to cancer drugs however, the underlying mechanisms must be elucidated and may require sustained AhR signaling. In this study, we conducted an integrative bioinformatics analysis to explore the role of AHR and LEPR in PCa, which revealed AHR and LEPR mRNA expression positively correlates in prostate cancer (P&amp;lt;0.05, Pearson: 0.68, R^2=0.46). The mRNA expression levels of AHR and LEPR in PCa tissue samples (i.e. solid tissue normal samples from individuals with cancer in TCGA, N=498) were analyzed using the cBioPortal and Xena online tools. We will further investigate if the decrease in drug response is seen in the presence of obesity-associated leptin concentrations. Further understanding of the potential interaction(s) between adipokines, AhR, and chemoresistance can promote improved treatments for patients with prostate cancer. Citation Format: Kofi Kyenku Khamit-Kush, Joann B. Powell, Jeffrey A. Handy, Nathan Bowen, Daqing Wu, Valerie Odero-Marah. Elevated aryl hydrocarbon receptor and leptin receptor expression correlates with prostate cancer progression and may be associated with obesity-associated leptin-mediated chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 394.
Abstract 1471: Over-expression of WW domain containing transcription regulator 1 (TAZ/WWTR1) in prostate cancer and its modulation by prostate-derived ETS factor (PDEF)
Authors: Praveen K. Jaiswal, Suman Mohajan, Sweaty Koul, Hari K. Koul
Journal: Cancer Research (2022)

Abstract Objective: WW domain containing transcription regulator 1 (TAZ/WWTR1), one of the two downstream effectors of the Hippo pathway, is known to regulate cancer cell proliferation, migration and apoptosis by acting as a transcriptional co-activator. Recently, we described altered expression of yes-associated protein (YAP1) (a paralog of TAZ) in prostate cancer. However, the expression and function of TAZ and its regulation in prostate cancer is not well characterized. In the present study, we profiled expression patterns of TAZ in clinical data sets of PCa and evaluated the effects of PDEF on TAZ phosphorylation in prostate cancer (PCa) cells in culture. Material &amp; Method: We analyzed the publicly available PCa datasets through Ualcan and c-Bioportal webservers. We transfected prostate cancer PC3 cells with PDEF or respective vector control. Protein levels of TAZ were analyzed by western blotting. Global changes in gene expression were analyzed using Affymetrix arrays followed by Gene Set Enrichment analysis. Results: Our analysis of publicly available PCa patient data in TCGA dataset, revealed a significant increase in TAZ mRNA levels in prostate cancer tissues as compared to normal prostate tissues (p=4.95E-08). Furthermore, we also found a significant gradual increase in TAZ mRNA expression during disease progression and metastasis. Our analysis of data sets in c-Bio portal revealed that patients with neuroendocrine PCa harbor much higher levels of TAZ mRNA as compared to CRPC phenotype. We also observed a negative correlation between PDEF and TAZ expression in CRPC/NEPC data set. We observed that the PC3 cells transfected with PDEF (PDEF-PC3) showed an increased phospho-TAZ as compared to the respective PC3 vector control (VC-PC3) suggesting that PDEF plays a critical role in modulating TAZ activity an important effector in Hippo signaling. Conclusions: These results provide first direct demonstration of elevated expression of TAZ in PCa, suggesting potential role of TAZ in prostate cancer. We also show for the first time increased TAZ phosphorylation in PCa cells by PDEF. Taken together with our recent work, our data suggest that PDEF modulates Hippo signaling by targeting both YAP1 and TAZ in PCa. Citation Format: Praveen K. Jaiswal, Suman Mohajan, Sweaty Koul, Hari K. Koul. Over-expression of WW domain containing transcription regulator 1 (TAZ/WWTR1) in prostate cancer and its modulation by prostate-derived ETS factor (PDEF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1471.
Abstract 2881: Proper priming of T cells is crucial for the anti-tumor effect of mPTX-35, an anti-TNFRSF25 agonist antibody
Authors: Dareen Sarhan, Lara Rabah, Vikas Tahiliani, Anh M. Trinh, Rahul R. Jasuja, Eric P. Dixon, Matthew Seavey, Vivek Verma, Seema Gupta, Samir N. Khleif
Journal: Cancer Research (2022)

Abstract TNFRSF25, also known as Death Receptor 3 (DR3), is a cell surface receptor of the tumor necrosis factor receptor superfamily (TNFRSF) which is expressed on T cells, innate lymphoid cells, and B cells. Upon binding with TL1A ligand, this co-stimulatory molecule induces T cell activation, leading either to inflammation or cell death. Mouse PTX-35 (mPTX-35) is a TNFRSF25 functional agonist derived from a CDR that was humanized and affinity matured, then fused to a mouse IgG1-Fc backbone. Since costimulatory agonist antibodies have shown limited efficacy in clinical trials, our aims were to (i) determine the anti-tumor efficacy of mPTX-35, (ii) elucidate any mechanisms of resistance, and (iii) identify immune conditions that provide effective anti-tumor immune responses to mPTX-35 treatment. We studied the anti-tumor immune effects of mPTX-35 in both cold and hot tumor models. In a TC-1 cold tumor, we found that treatment with an anti-TNFRSF25 agonist antibody does not affect tumor growth or survival. In contrast, vaccination with an E7 antigen-specific vaccine leads to an environment that reverses primary resistance to the agonist antibody, inhibiting the tumor growth, and enhancing overall survival. Interestingly, we found that similar to other co-stimulatory agonist molecules, the immune effects of the anti-TNFRSF25 agonist are dose-dependent with lower (0.2 mg/kg) and higher (5 mg/kg) doses of mPTX-35 showing a reduced anti-tumor response than a dose of 1 mg/kg, resulting in a bell-shaped response in all tumor models. Similar immune-mediated anti-tumor effects of mPTX-35 were found in a CT26 (hot) tumor model. In conclusion, these results show that anti-TNFRSF25 agonist antibody demonstrates high anti-tumor efficacy in tumors that are infiltrated with T cells while the absence of properly antigen activated CD8 T cells (such as in cold tumors) incurs primary resistance to TNFRSF25 agonist that is reversed by proper priming of CD8 T cells. These results highlight the importance of optimal priming to limit primary resistance mechanisms and drive an efficacious immune response via the TNSFR25 axis. Citation Format: Dareen Sarhan, Lara Rabah, Vikas Tahiliani, Anh M. Trinh, Rahul R. Jasuja, Eric P. Dixon, Matthew Seavey, Vivek Verma, Seema Gupta, Samir N. Khleif. Proper priming of T cells is crucial for the anti-tumor effect of mPTX-35, an anti-TNFRSF25 agonist antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2881.
Abstract CT567: Comprehensive measures of COVID-19 vaccine efficacy in adolescent cancer patients: Results from SerOzNET
Authors: Eva Segelov, Amy Body, Stuart Turville, Corey Smith, Katie Lineburg, Sudha Rao, Robert McCuaig, Stephen Opat, Zin Niang, Luxi Lal, Vi Luong, Hesham Abdulla, Veronica Aedo Lopez, Bhavna Padhye, Noemi Fuentes Bolanos, Antoinette Anazodo, Raina MacIntyre, Peter Downie, Tracey O'Brien, Elizabeth Ahern
Journal: Cancer Research (2022)

Abstract The authors did not submit an updated abstract. The original abstract should be considered final. Citation Format: Eva Segelov, Amy Body, Stuart Turville, Corey Smith, Katie Lineburg, Sudha Rao, Robert McCuaig, Stephen Opat, Zin Niang, Luxi Lal, Vi Luong, Hesham Abdulla, Veronica Aedo Lopez, Bhavna Padhye, Noemi Fuentes Bolanos, Antoinette Anazodo, Raina MacIntyre, Peter Downie, Tracey O'Brien, Elizabeth Ahern. Comprehensive measures of COVID-19 vaccine efficacy in adolescent cancer patients: Results from SerOzNET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT567.
Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA
Authors: Dianne H.K. van Dam-Nolen, Martine T.B. Truijman, Anja G. van der Kolk, Madieke I. Liem, Floris H.B.M. Schreuder, Eric Boersma, Mat J.A.P. Daemen, Werner H. Mess, Robert J. van Oostenbrugge, Antonius F.W. van der Steen, Daniel Bos, Peter J. Koudstaal, Paul J. Nederkoorn, Jeroen Hendrikse, Aad van der Lugt, M. Eline Kooi
Journal: JACC. Cardiovascular imaging (2022)

BACKGROUND Patients with symptomatic carotid stenosis are at high risk for recurrent stroke.The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%).Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk.Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making.OBJECTIVES The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging.METHODS The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-tomoderate carotid stenosis in a prospective multicenter cohort study.Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years.The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA).Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint.Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTSDuring 5.1 years follow-up, 37 patients reached the clinical endpoint.IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44]for IPH; HR: 1.07 [95% CI:1.00-1.15]for total plaque volume per 100 mL increase).Ulcerations and proportion of calcifications were not statistically significant determinants.Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78).CONCLUSIONS IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis.These plaque characteristics improve current decision making.Validation studies to implement plaque characteristics in clinical scoring tools are needed.(PARISK:
Abstract 1147: A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer
Authors: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun
Journal: Cancer Research (2022)

Abstract About 43,600 women in the U.S. are expected to die in 2021 from breast cancer. Triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, is diagnosed by exclusion of expression and/or amplification of three biomarkers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]).Characterized by a high risk of relapse (one half of patients with early stages experience recurrence), short overall survival and progression-free survival (life expectancy of few months after failure of first-line chemotherapy), TNBC represents a high unmet medical need. Galectin-3 plays multiple roles in tumor initiation and development via a variety of cellular processes, spanning from angiogenesis to tumor migration. Galectin-3 (Gal3) expression is induced in TNBC patients and highly correlates with poor survival, as shown by our and others’ bioinformatics analysis from public database. We recently discovered and patented a series of antibodies with high specificity and affinity for Gal3, one of which is currently tested in human volunteers. This clinical candidate has shown superior pharmacokinetic properties and clean toxicity profile in GLP studies on non-human primates. Here, we show that anti-Gal3 inhibit both anchorage dependent and independent growth of TNBC cells, as well as Gal3-induced escape from NK cell killing. Also, anti-Gal3 proved to be efficacious in in vivo studies, where TNBC cells were implanted in mammary fat pads of mice and tumor progression, measured as growth of primary mass and presence of metastatic nodules in the lungs, was followed during the two months of treatment. The results presented herein support the conclusion that our therapeutic modality could offer an alternative promising treatment of TNBC. Citation Format: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1147.
Abstract 868: Splicing factor mutant lung cancers: A comprehensive molecular and clinicopathologic characterization
Authors: Guilherme Harada, Christina J. Falcon, Fernando C. Santini, Jason C. Chang, Soo R. Yang, Maria E. Arcila, Natasha Rekhtman, Alexander Drilon
Journal: Cancer Research (2022)

Abstract Background: Splicing factor mutations can drive oncogenesis in different cancer types. More importantly, strategies to target splicing-dependent cancers have been developed, including PRMT5 inhibition which regulates alternative splicing and targets posttranslational modification; PRMT5 inhibitors are in ongoing phase I clinical trials. The characterization of splicing alterations in non-small cell lung cancer (NSCLC) has not been extensively studied and represents an unmet need. Methods: Based on previously known genes associated with splicing alterations, genomic and clinicopathologic data from NSCLC patients with hotspot or loss of function mutations identified by next-generation sequencing in the splicing factors SF3B1, SRSF2, U2AF1, ZRSR2, RBM10, and FUBP1 were explored. Results: Among 626 NSCLC patients with at least one splicing mutation, 85% (529/626) also harbored a co-occurring oncogenic driver, such as alterations involving KRAS (60%; 319/529), EGFR (25%;132/529), MET (5%; 27/529), BRAF(4%; 24/529), and ERBB2 (3%; 17/529). After excluding patients with concurrent drivers, 97 splicing-factor-mutant NSCLCs were identified, with 80 (82%) adenocarcinomas and 6 (6%) squamous cell carcinomas. The median age was 71 years (43-89). Forty-nine patients (51%) were female. Sixty patients (62%) were diagnosed with stage I-III disease. Eleven (11%) were never smokers, while 86 (89%) were former/current smokers, with a median of pack years of 30. The median tumor mutational burden was 7.9 mut/Mb (0.9-90.4). Regarding splicing factor mutations, sixty-two patients (64%) had nonsense or splice-site RBM10 mutations, 17 (17%) had missense hotspot SF3B1 mutations, 16 (16%) had hotspot missense U2AF1 mutations, and 7 (7%) had nonsense, splice-site, or hotspot missense FUBP1 mutation. No patients with ZRSR2 or SRSF2 were identified. Only three patients presented concurrent splicing mutations: one with two SF3B1 mutations; one with RBM10 and SF3B1 mutations; and one with U2AF1 and SF3B1 mutations. Conclusion: Most patients with splicing factor mutant NSCLCs are smokers whose cancers commonly harbor RBM10 mutations and higher TMB compared to other driver-positive cancers. The characterization of this profile is key to identifying appropriate patients for ongoing targeted therapy trials for this population. Citation Format: Guilherme Harada, Christina J. Falcon, Fernando C. Santini, Jason C. Chang, Soo R. Yang, Maria E. Arcila, Natasha Rekhtman, Alexander Drilon. Splicing factor mutant lung cancers: A comprehensive molecular and clinicopathologic characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 868.
Abstract 5771: The refined stratification of receptor tyrosine kinase fusions in lung cancer
Authors: Chaoyang Liang, Lin Li, Xiaofang Liu, Qiuhua Liu, Baoming Wang, Chunyang Wang, Tonghui Ma, Fanlu Meng
Journal: Cancer Research (2022)

Abstract Background: The overall survival of patients with the actionable receptor tyrosine kinase (TRK) fusions can be significantly prolonged after taking targeted kinase inhibitors. However, the outcomes are variable due to the different fusion types of the same driver gene. Method: Formalin fixed paraffin embedded tissues from patients with lung cancer between March 2018 and September 2021 were performed by using next generation sequencing (NGS) at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments. Results: In a large cohort of 3768 patients with lung cancer, 348 cases harboring the actionable TKR fusions, including ALK, ROS1, RET, EGFR, MET, BRAF, NTRK1/2/3. TRK fusions can be divided into three types based on the breakpoints, partners and fusion models: single 3’ fusions, nonreciprocal fusions with the intact tyrosine kinase domain (TKD); single 5’ fusions, reciprocal fusions with the incomplete TKD; complex fusions, nonreciprocal/reciprocal fusions or nonreciprocal fusions with different partners. At the gene level, 58% (203 of 348) of TRK fusions were ALK, among which 71% of single 3’ ALK (144 of 203), 3% of single 5’ ALK (6 of 203) and 26% of complex fusions (53 of 203) were included. ROS1 fusions accounted for 14% (50 of 348) of all TRK fusions, and the proportions of single 3’ fusions, single 5’ fusions and complex fusions were 60% (30 of 50), 6% (3 of 50) and 34% (17 of 50), respectively. RET captured 19% (66 of 348) TRK fusions with 70% of single 3’ RET (46 of 66), 5% of single 5’ RET (3 of 66) and 26% of the complex fusions (17 of 66). EGFR owned 3% (9 of 348) with 33% of single 3’ EGFR (3 of 9), 33% of single 5’ EGFR (3 of 9) and 33% of the complex (3 of 9). MET, BRAF and NTRK1/2/3 shared the rest 5% of total fusions without complex type. Conclusion: Our research shows different types of TRK fusions in Chinese lung cancer patients, which can help guide the precise treatment in clinical. Citation Format: Chaoyang Liang, Lin Li, Xiaofang Liu, Qiuhua Liu, Baoming Wang, Chunyang Wang, Tonghui Ma, Fanlu Meng. The refined stratification of receptor tyrosine kinase fusions in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5771.